Enrollment Status:Open (Enrolling)Gender: BothConditions: Histological Evidence of Metastatic Clear Cell Renal Cell Carcinoma, That Has Been Previously Treated With 1-3 Prior Regimens. Phase 1 Only, Any Number of Prior Regimens, With Evidence of Progressive Disease on or Within 6 Months, of Discontinuing Sunitinib, Sorafenib or Pazopanib. Previous, Therapy With Bevacizumab, IL2, or Interferon Are Permitted.

Trial Information

This protocol describes a multicenter phase I/II trial of RAD001 in combination with HCQ
(phase I anticipated n=6-12) with a 35 patient phase II trial in patients with previously
treated (1-3 prior regimens) advanced renal cell carcinoma. The preclinical rationale for
this combination is extensive, the safety of HCQ combination strategies has been
established, and effective autophagy PD, and PK assays are available to guide development.
The practical advantage of combination with HCQ is that this drug is off patent,
commercially available, and is IND exempt. The institutions involved have combined 11
clinical protocols open for accrual involving HCQ, so regulatory approval will be rapid.
There are no competing HCQ protocols for advanced renal cell carcinoma. As described in the
sample size justification we are setting a high threshold to consider RAD001 + HCQ active
since there are many competitors and other potential rational combinations. The 35 patient
sample size is designed as a 2 stage phase II trial that will guide the go/no-go decision
regarding the conduct of a followup randomized study to definitively prove efficacy. The
primary (6 month PFS) and secondary outcomes (response rate, toxicity rates, correlative
endpoints) will be analyzed for the entire group, and for patient populations stratified by
number of prior therapies. The phase I portion of this trial is anticipated to be short,
based on our experience from other HCQ trials. As a safety measure we have included
intermediate dose levels which will only be used if there are Dose Limiting Toxicities
(DLTs). Since we have seen responses at lower doses of HCQ in other trials, and because
frequently over months HCQ dose is lowered from Maximum Tolerated Dose (MTD) doses in many
trials because of nausea and anorexia, we would like to have some data on renal cell
patients treated at the lower dose levels. If there is activity demonstrated at lower doses,
this would be informative for dose modification decisions in patients treated on the dose
expansion. The patient population for this trial, including the phase I dose escalation
portion is advanced renal cell carcinoma with 1-3 prior treatments.

Inclusion Criteria:

- 2 Phase I only, any number of prior regimens with evidence of progressive
disease 3 Patients must have at least one measurable site of disease according
to RECIST criteria that has not been previously irradiated. If the patient has
had previous radiation to the marker lesion(s), there must be evidence of
progression since the radiation

- 10 INR and PTT 1.5. (Anticoagulation is allowed if target INR 1.5 on a stable
dose of warfarin or on a stable dose of anticoagulant for 2 weeks at time of
randomization.) Adequate renal function: serum creatinine 2.0 x ULN or CrCl 60
11 Fasting serum cholesterol 300 mg/dL OR 7.75 mmol/L AND fasting triglycerides
2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the
patient can only be included after initiation of appropriate lipid lowering
medication.

12 Signed informed consent

Exclusion Criteria:

- 1. Patients currently receiving anticancer therapy or who have received anticancer
therapy within 4 weeks of the start of study drug (including chemotherapy, radiation
therapy, antibody based therapy, etc.). To prevent explosive disease progression
associated with angigoenic rebound from impacting the results of this study, patients
who have received prior antiangiogenic therapy in the form of a small molecule
multikinase inhibitor or bevacizumab must be off prior therapy for 1 week and have
antiangiogenic therapy-associated AEs resolve to grade 2 before starting study
treatment.

2 Patients, who have had a major surgery or significant traumatic injury within 4
weeks of start of study drug, patients who have not recovered from the side effects
of any major surgery or patients that may require major surgery during the course of
the study 3 Prior treatment with any investigational drug within the preceding 4
weeks .4 Patients receiving chronic, systemic treatment with corticosteroids or
another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

5 Patients should not receive immunization with attenuated live vaccines within one
week of study entry or during study period

- 6 Uncontrolled brain or leptomeningeal metastases, including patients who
continue to require glucocorticoids for brain or leptomeningeal metastases 7
Other malignancies within the past 3 years except for adequately treated
carcinoma of the cervix or basal or squamous cell carcinomas of the skin, Stage
I resected melanoma, DCIS, squamous cell carcinoma of the skin, resected, basal
cell carcinoma, indolent prostate cancer 8 Patients who have any severe and/or
uncontrolled medical conditions or other conditions that could affect their
participation in the study such as:

- 9 Symptomatic congestive heart failure of New York heart Association Class III
or IV 10 Unstable angina pectoris, myocardial infarction within 6 months of
start of study drug, serious uncontrolled cardiac arrhythmia or any other
clinically significant cardiac disease 11 Severely impaired lung function with a
previously documented spirometry and DLCO that is 50% of the normal predicted
value and/or 02 saturation that is 88% or less at rest on room air 12
Uncontrolled diabetes as defined by fasting serum glucose 1.5 x ULN

- 17 Patients with an active, bleeding diathesis 18 Female patients who are
pregnant or breast feeding, or adults of reproductive potential who are not
using effective birth control methods. If barrier contraceptives are being used,
these must be continued throughout the trial by both sexes. Hormonal
contraceptives are not acceptable as a sole method of contraception. (Women of
childbearing potential must have a negative urine or serum pregnancy test within
7 days prior to administration of RAD001) 19 Patients who have received prior
treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).(Phase I
prior mTOR inhibitor allowed) 20 Patients with a known hypersensitivity to
RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its
excipients 21 History of noncompliance to medical regimens

- 22 Patients unwilling to or unable to comply with the protocol .23 A detailed
assessment of Hepatitis B/C medical history and risk factors must be done at
screening for all patients. HBV DNA and HCV RNA PCR testing are required at
screening for all patients with a positive medical history based on risk factors
and/or confirmation of prior HBV/HCV infection.

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